The present project has been designed to study the mechanism by which different toxic chemicals cause an ultimate irreversible damage. The working hypothesis is that although the actual toxicity of a chemical is specific to the nature of the chemical, the cell reaches a threshold limit when it can no longer overcome the toxic effects of the chemical and, at that time, some common denominator mediates the irreversible damage to the cell. There have been controversial reports regarding the role of calcium, as the common denominator, in lethal cell damage. Previous studies of the principal investigator established a progressive rise in the intracellular calcium levels and alterations in the intracellular calcium uptake processes. These changes increased with toxicity till the time of death. Similar results were obtained in isolated perfused rat liver experiments. These studies, although do not confirm the role of calcium as a common denominator, do give an indication that in the in vivo systems, plasma membrane damage (leading to high intracellular calcium levels) associated with another factor might actually decide the irreversibility. Measurement of this threshold is the objective of the present project. It is based upon the hypothesis that disturbances in mitochondrial activity (reduced mitochondrial oxygen consumption and changes in the redox state) associated with perturbations in the intracellular calcium homeostasis might be involved in mediating the final irreversible damage to the cell. Right experimental protocol to study these changes is very important. The studies proposed in the present project will be carried out in two basic sets: (1) The doses will be adjusted to produce progressive toxicity leading to death in 48 hours. (2) Progressive toxicity with a peak at 36 hours and apparent recovery by 120 hours. The above mentioned mechanism will be studied in three different tissues: liver, kidney and lungs using three different known chemical toxins: CC1-4, CHC1-3 and cadmium respectively. The project will help a great deal in improving the research environment of the college and more undergraduate students will develop interest in the independent study projects.